Meet a New NSCLC Target: c-MET

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Non-small cell lung cancer (NSCLC) is the most common type of lung cancer in the United States, accounting for about 85% of all lung carcinomas. It is the leading cause of cancer death in the U.S. Current treatments include lobectomy (surgery to remove the part of the lung affected by the cancer), chemotherapy, radiation therapy, targeted therapy, immunotherapy or a combination of these modalities.

Although recent advances in immunotherapy and targeted therapy have done much to improve the prognosis of people with NSCLC, not all patients have benefited. Researchers and drug developers are looking for new vulnerabilities that treatments can use to kill NSCLC cells or stifle their runaway cancerous growth.

The c-mesenchymal-epithelial transition factor (c-MET) is the hepatocyte growth factor (HGF) tyrosine kinase receptor encoded by the MET oncogene. HGF and c-MET binding contributes to excessive cell proliferation and tumor development. In several types of cancer, including NSCLC, the MET gene is aberrantly amplified or mutated, resulting in rapid cancer cell proliferation, tumor progression and metastasis. The c-MET protein is disproportionately over-expressed in NSCLC tumors and associated with poor prognosis.

Given these discoveries, researchers believe that therapies targeting c-MET may show promise in treating NSCLC. To date, no NSCLC treatment specifically targeting the c-MET protein exists. Several drug companies aim to rectify that, and two have therapies targeting c-MET in phase 3
clinical trials.

Savolitinib

AstraZeneca’s savolitinib is an oral investigational c-MET-selective tyrosine kinase inhibitor under development for treating various types of cancer, including NSCLC. In June 2021, savolitinib received conditional approval in China, where it is currently marketed under the brand name Orpathys.

In the U.S., the agent is in phase 3 trials for the potential treatment of NSCLC with MET exon 14 skipping mutations. The phase 2 SAVANNAH trial showed an objective response rate (ORR) of 49% in patients who received Tagrisso (osimertinib) plus savolitinib and who had epidermal growth factor receptor-mutated (EGFRm) NSCLC with high levels of c-MET overexpression.

The phase 3 trial, called SAFFRON,is an open-label study evaluating the safety and efficacy of the savolitinib-Tagrisso combination compared with platinum-based chemotherapy in adults with EGFRm NSCLC with c-MET overexpression or amplification and disease progression after treatment with Tagrisso. The study’s primary outcome is progression-free survival, and secondary outcomes include overall survival and ORR. The primary completion date is estimated to be in May 2025.

Many patients with EGFRm NSCLC eventually develop resistance to EGFR-targeted treatments, such as Tagrisso. The most common pathway for resistance is through the c-MET protein. Researchers say they are optimistic about c-MET-targeted approaches in combating resistance.

Myung-Ju Ahn, M.D., Ph.D., professor of hemato-oncology at Samsung Medical Center, Sungkyunkwan University School of Medicine in Seoul, South Korea, and principal investigator in the SAVANNAH trial, said in a news release, “Acquired resistance to targeted therapy and disease progression are difficult realities for most patients with EGFR-mutated non-small cell lung cancer. These preliminary SAVANNAH results potentially support a novel approach for identifying patients with MET overexpression and/or amplification who are most likely to benefit from a MET-directed therapy like savolitinib.”

Ahn add that"they also suggest that with the right biomarker testing strategy, MET may be a more prevalent target among resistant patients than previously understood, supporting further investigation of the osimertinib (Tagrisso) plus savolitinib regimen.”

Telisotuzumab vedotin (Teliso-V)

Teliso-V (telisotuzumab vedotin) is a potential first-in-class antibody-drug conjugate targeting the c-MET protein. It is being developed by AbbVie for use in several cancers, including NSCLC. After positive results from the phase 2 LUMINOSITY study, Teliso-V was granted breakthrough therapy designation by the FDA for the treatment of advanced or metastatic NSCLC in patients with high levels of c-MET overexpression and disease progression after platinum-based treatment.

The investigational treatment is in the TeliMET phase 3 trial evaluating the safety and efficacy of Teliso-V versus docetaxel in adults with previously treated NSCLC with c-MET overexpression. The primary outcomes are progression-free survival and overall survival. Secondary outcomes include ORR and duration of response. Preliminary results are anticipated in June 2025.

Rosanna Sutherby, Pharm.D., an independent medical writer and community pharmacist in High Point, North Carolina, is a regular contributor to Managed Healthcare Executive.